The specific switching-off of gene expression by complementary nucleic acids, so-called antisense oligonucleotides, represents a-novel therapeutic approach. Possible applications-extend from the treatment of vital infections through to the therapy of cancer (S. Agrawal, Tibtech 10, 152 (1992); W. James, Antiviral Chemistry & Chemotherapie 2, 191 (1991); B. Calabretta, Cancer Research 51, 4504 (1991)). The control of gene expression is effected at the level of DNA and RNA and is achieved even with unmodified oligonucleotides (C. Helene, Anti-Cancer Drug Design 6, 569 (1991); E. Uhlmann, A. Peymann, Chemical Reviews 90, 543 (1990)) . However, owing to insufficient stability towards enzymes and inadequate uptake into cellular systems, these oligonucleotides are not suitable for therapeutic applications. Therapeutic applications require chemically modified antisense oligonucleotides.
Oligonucleotides possessing a modified internucleotide phosphate or a phosphate-free internucleotide linkage have been systematically investigated in many studies; however, their synthesis has proved to be very elaborate and observed therapeutic effects to be unsatisfactory (E. Uhlmann, A. Peymann, Chemical Reviews 90, 543 (1990)).
One alternative to modifying or substituting the phosphate group in nucleic acids is completely to replace ribose and phosphate by other backbones. This concept was realized for the first time by Pitha et al., who replaced ribose phosphate by poly-N-vinyl derivatives, leading to so-called "plastic DNA" (J. Pitha, P.O.P. Ts'O, J. Org. Chem. 33, 1341 (1968); J. Pitha, J. Adv. Polym. Sci. 50, 1 (1983)). However, this does not permit the specific construction of defined sequences.
The synthesis of defined sequences is achieved if, for example, a polyamide backbone, which is built up step-wise in analogy with conventional peptide synthesis (M. Bodanszky, Principles of Peptide Synthesis, Springer, Berlin 1984), is used in place of sugar phosphate. This concept has been realized in differing ways by a variety of research groups (J. E. Summerton et al. WO 86/05518; R. S. Varma et al. WO 92/18518; O. Buchardt et al. WO 92/20702; H. Wang, D. D. Weller, Tetrahedron Letters 32, 7385 (1991); P. Garner, J. U. Yoo, Tetrahedron Letters 34, 1275 (1993); S.-B. Huang, J. S. Nelson, D. D. Weller; J. Org. Chem. 56, 6007 (1991)).
Polyamide nucleic acids are likewise suitable for diagnostic and molecular-biological applications (Buchardt et al. WO 92/20703).